tbuckley/cabot-search huggingface dataset:
Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study
Authors: Stephen A. Harrison, Federico Perez Manghi, William B. Smith, Diana Alpenidze, Diego Aizenberg, Naomi Klarenbeek, Chi-Yi Chen, Eli Zuckerman, Eric Ravussin, Phunchai Charatcharoenwitthaya, Pin-Nan Cheng, Helena Katchman, Samuel Klein, Ziv Ben-Ari, Anisha E. Mendonza, Yiming Zhang, Miljen Martic, Shenglin Ma, Sheena Kao, Sandra Tanner, Alok Pachori, Michael K. Badman, YanLing He, Chinweike Ukomadu, Eric Sicard
Journal: Nature Medicine (2022)
Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis
Authors: Mengqi Zhu, Sainan Min, Xiangdi Mao, Yuan Zhou, Yan Zhang, Wei Li, Li Li, Liling Wu, Xin Cong, Guangyan Yu
Journal: International Journal of Oral Science (2022)

Abstract Immunoglobulin G4-related sialadenitis (IgG4-RS) is an immune-mediated fibro-inflammatory disease and the pathogenesis is still not fully understood. The aim of this study was to explore the role and mechanism of interleukin-13 (IL-13) in the cellular senescence during the progress of IgG4-RS. We found that the expression of IL-13 and IL-13 receptor α1 (IL-13Rα1) as well as the number of senescent cells were significantly higher in the submandibular glands (SMGs) of IgG4-RS patients. IL-13 directly induced senescence as shown by the elevated activity of senescence-associated β-galactosidase (SA-β-gal), the decreased cell proliferation, and the upregulation of senescence markers (p53 and p16) and senescence-associated secretory phenotype (SASP) factors (IL-1β and IL-6) in SMG-C6 cells. Mechanistically, IL-13 increased the level of phosphorylated signal transducer and activator of transcription 6 (p-STAT6) and mitochondrial-reactive oxygen species (mtROS), while decreased the mitochondrial membrane potential, ATP level, and the expression and activity of superoxide dismutase 2 (SOD2). Notably, the IL-13-induced cellular senescence and mitochondrial dysfunction could be inhibited by pretreatment with either STAT6 inhibitor AS1517499 or mitochondria-targeted ROS scavenger MitoTEMPO. Moreover, IL-13 increased the interaction between p-STAT6 and cAMP-response element binding protein (CREB)-binding protein (CBP) and decreased the transcriptional activity of CREB on SOD2. Taken together, our findings revealed a critical role of IL-13 in the induction of salivary gland epithelial cell senescence through the elevated mitochondrial oxidative stress in a STAT6–CREB–SOD2-dependent pathway in IgG4-RS.
2022 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty
Authors: Susan M. Goodman, Bryan D. Springer, Antonia F. Chen, Marshall Davis, David R. Fernandez, Mark Figgie, Heather Finlayson, Michael D. George, Jon T. Giles, Jeremy Gililland, Brian Klatt, Ronald MacKenzie, Kaleb Michaud, Andy Miller, Linda Russell, Alexander Sah, Matthew P. Abdel, Beverly Johnson, Lisa A. Mandl, Peter Sculco, Marat Turgunbaev, Amy S. Turner, Adolph Yates, Jasvinder A. Singh
Journal: Arthritis & Rheumatology (2022)

Objective To develop updated guidelines for the perioperative management of disease‐modifying medications for patients with rheumatic diseases, specifically those with inflammatory arthritis (IA) and those with systemic lupus erythematosus (SLE), undergoing elective total hip arthroplasty (THA) or elective total knee arthroplasty (TKA). Methods We convened a panel of rheumatologists, orthopedic surgeons, and infectious disease specialists, updated the systematic literature review, and included currently available medications for the clinically relevant population, intervention, comparator, and outcomes (PICO) questions. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence and the strength of recommendations using a group consensus process. Results This guideline updates the 2017 recommendations for perioperative use of disease‐modifying antirheumatic therapy, including traditional disease‐modifying antirheumatic drugs, biologic agents, targeted synthetic small‐molecule drugs, and glucocorticoids used for adults with rheumatic diseases, specifically for the treatment of patients with IA, including rheumatoid arthritis and spondyloarthritis, those with juvenile idiopathic arthritis, or those with SLE who are undergoing elective THA or TKA. It updates recommendations regarding when to continue, when to withhold, and when to restart these medications and the optimal perioperative dosing of glucocorticoids. Conclusion This updated guideline includes recently introduced immunosuppressive medications to help decision‐making by clinicians and patients regarding perioperative disease‐modifying medication management for patients with IA and SLE at the time of elective THA or TKA.
Abstract 633: Delineating tumor-neural communication in brain metastasis with spatiotemporal transcriptomic analysis and multi-cellular crosstalk modeling
Authors: Xin Wang, Ying Zhu, Jianting Sheng, Hong Zhao, Stephen Wong
Journal: Cancer Research (2022)

Abstract Brain metastases are diagnosed in 20-40% of all cancer patients. Despite the advancements in neurosurgery, radiotherapy, and chemotherapy, one-year survival of metastatic brain tumor patients still within a single digit such that brain metastases constitute about 20% of annual cancer deaths. These facts clearly indicate a critical need for better understanding of mechanisms that promote the growth of brain metastases. Emerging data, including ours, indicate that different types of metastatic cancer cells leverage dissimilar sets of neurotransmitters to favor their outgrowth in the brain. However, there are over sixty types of neurotransmitters in the brain being synthesized and released by various types of neural cells, we need a systemic investigation of how they mediate the pathogenesis of brain metastases in concert. Since neurotransmitters, gliotransmitters, neurotrophic factors, and neural cytokines, called neuroactive substances, are the most abundant and key intercellular communication signals in the brain, we hypothesize that tumor cells leverage these neuroactive substances to assimilate into neural circuitry via communicating with neural cells including neurons, astrocytes, microglia, oligodendrocyte, and others, in promoting the vicious circle of tumor-neural crosstalk during brain metastasis development. By performing spatial transcriptomics analysis on mouse brain sections bearing metastatic tumors, we found that tumor lesions at different locations and even tumor-surrounding areas in the brain regions could be differentiated into different cellular clusters based on gene transcriptomic expressions. We further predicted several paracrine and autocrine signaling between and within tumors as well as tumor-surrounding neural niches in different tumor locations (e.g., centers or edges), of different tumor sizes, and at various tumor development stages, using our Cell-Cell Communication Explorer (CCC-Explorer) modeling software. Functional experiments were conducted to demonstrate that cell type-specific depletion of the secreted NSs deactivated the activities of corresponding receptors and downstream signaling in co-cultured metastatic brain tumor cells. Characterizing spatiotemporal tumor-neural crosstalk in the brain metastatic niche would provide a new strategy in the development of novel and effective therapeutics of brain metastases. Citation Format: Xin Wang, Ying Zhu, Jianting Sheng, Hong Zhao, Stephen Wong. Delineating tumor-neural communication in brain metastasis with spatiotemporal transcriptomic analysis and multi-cellular crosstalk modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 633.
AML, NOS and AML-MRC as defined by multilineage dysplasia share a common mutation pattern which is distinct from AML-MRC as defined by MDS-related cytogenetics
Authors: Irene Fuhrmann, Miriam Lenk, Torsten Haferlach, Anna Stengel, Stephan Hutter, Constance Baer, Manja Meggendorfer, Wolfgang Kern, Claudia Haferlach
Journal: Leukemia (2022)
Abstract 634: Mutation agnostic diagnosis of clonal hematopoiesis of indeterminate potential using fluctuating methylation clocks
Authors: Ryan O. Schenck, Niels A. Jakobsen, Virginia Turati, Darryl Shibata, Paresh Vyas, Simon Leedham, Alexander R. Anderson
Journal: Cancer Research (2022)

Abstract Clonal hematopoiesis (CH), such as clonal hematopoiesis of indeterminant potential (CHIP), is diagnosed based on somatic genomic alterations in the absence of hematologic malignancy. At present, CHIP is diagnosed using peripheral blood where putative driver point mutations and small insertions/deletions whose variant allele frequency is greater or equal to two percent. Generally, the prevalence of CH increases as an individual ages and conveys a risk for progression to a malignancy. Previously, we developed a method using fluctuating CpG (fCpG) sites to serve as a fluctuating methylation clock to uncover stem cell dynamics in glandular tissues and orthogonally validated our method using publicly available datasets of human blood from normal cohorts and malignant cohorts. Here we expand on this work by presenting 38 new patients with distinct VAF groups from 1-2% VAF up to greater than 10% VAF for putative drivers with corresponding DNA methylation profiles using the Illumina EPIC array platform. We identify fCpG from our normal and CHIP cohorts to train and validate a machine learning method that allows us to diagnose CHIP without DNA sequencing. This method allows for the identification of patients who may have CH driven by structural variants such as copy number variants. We use this method to examine a cohort of 656 normal patients without evidence of CHIP based on mutation showing that we identify the presence of CHIP roughly a third of these patients. Clonal hematopoiesis is driven by the underlying hematopoietic stem cells of an unknown quantity, with estimates for stim cell numbers differing by orders of magnitude.Finally, using a mechanistic model of clonal hematopoeisis and fCpGs we examine the temporal ability to diagnose CHIP given single and multiple expanding clones. We illustrate that multiple driver mutations within the same clone leads to an increased detection ability with an increased expansion rate (i.e. fitness) and in cases where drivers are found in separate, competing clones. Citation Format: Ryan O. Schenck, Niels A. Jakobsen, Virginia Turati, Darryl Shibata, Paresh Vyas, Simon Leedham, Alexander R. Anderson. Mutation agnostic diagnosis of clonal hematopoiesis of indeterminate potential using fluctuating methylation clocks [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 634.
Tipping the balance: toward rational combination therapies to overcome venetoclax resistance in mantle cell lymphoma
Authors: Yvonne J. Thus, Eric Eldering, Arnon P. Kater, Marcel Spaargaren
Journal: Leukemia (2022)

Abstract Mantle cell lymphoma (MCL), an aggressive, but incurable B-cell lymphoma, is genetically characterized by the t(11;14) translocation, resulting in the overexpression of Cyclin D1. In addition, deregulation of the B-cell lymphoma-2 (BCL-2) family proteins BCL-2, B-cell lymphoma-extra large (BCL-X L ), and myeloid cell leukemia-1 (MCL-1) is highly common in MCL. This renders these BCL-2 family members attractive targets for therapy; indeed, the BCL-2 inhibitor venetoclax (ABT-199), which already received FDA approval for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), shows promising results in early clinical trials for MCL. However, a significant subset of patients show primary resistance or will develop resistance upon prolonged treatment. Here, we describe the underlying mechanisms of venetoclax resistance in MCL, such as upregulation of BCL-X L or MCL-1, and the recent (clinical) progress in the development of inhibitors for these BCL-2 family members, followed by the transcriptional and (post-)translational (dys)regulation of the BCL-2 family proteins, including the role of the lymphoid organ microenvironment. Based upon these insights, we discuss how rational combinations of venetoclax with other therapies can be exploited to prevent or overcome venetoclax resistance and improve MCL patient outcome.
Management and Outcomes of Severe Hypoglycemia Treated by Emergency Medical Services in the U.S. Upper Midwest
Authors: Lucas A. Myers, Kristi M. Swanson, Amy E. Glasgow, Rozalina G. McCoy
Journal: Diabetes Care (2022)

OBJECTIVE To examine factors associated with emergency department (ED) transport after hypoglycemia treated by emergency medical services (EMS) and assess the impact of ED transport on severe hypoglycemia recurrence. RESEARCH DESIGN AND METHODS We retrospectively analyzed electronic health records of a multistate advanced life support EMS provider and an integrated healthcare delivery system serving an overlapping geographic area in the upper Midwest. For adults with diabetes treated by EMS for hypoglycemia between 2013 and 2019, we examined rates of ED transport, factors associated with it, and its impact on rates of recurrent hypoglycemia requiring EMS, ED, or hospital care within 3, 7, and 30 days. RESULTS We identified 1,977 hypoglycemia-related EMS encounters among 1,028 adults with diabetes (mean age 63.5 years [SD 17.7], 55.2% male, 87.4% non-Hispanic White, 42.4% rural residents, and 25.6% with type 1 diabetes), of which 46.4% resulted in ED transport (31.1% of calls by patients with type 1 diabetes and 58.0% of calls by patients with type 2 diabetes). Odds of ED transport were lower in patients with type 1 diabetes (odds ratio [OR] 0.44 [95% CI 0.31–0.62] vs. type 2 diabetes) and higher in patients with prior ED visits (OR 1.38 [95% CI 1.03–1.85]). Within 3, 7, and 30 days, transported patients experienced recurrent severe hypoglycemia 2.8, 5.2, and 10.6% of the time, respectively, compared with 7.4, 11.2, and 22.8% of the time among nontransported patients (all P &amp;lt; 0.001). This corresponds to OR 0.58 (95% CI 0.42–0.80) for recurrent severe hypoglycemia within 30 days for transported versus nontransported patients. When subset by diabetes type, odds of recurrent severe hypoglycemia among transported patients were 0.64 (95% CI 0.43–0.96) and 0.42 (95% CI 0.24–0.75) in type 1 and type 2 diabetes, respectively. CONCLUSIONS Transported patients experienced recurrent hypoglycemia requiring medical attention approximately half as often as nontransported patients, reinforcing the importance of engaging patients in follow-up to prevent recurrent events.
Abstract 6339: Deep plasma proteomics at scale enabling proteogenomic analyses in a lung cancer (NSCLC) study
Authors: Mahdi Zamanighomi, Harendra Guturu, Jian Wang, Amir Alavi, Tristan Brown, Daniel Hornburg, Moaraj Hasan, Shadi Ferdosi, Khatereh Motamedchaboki, Margaret Donovan, Theodore Platt, Ryan Benz, Asim Siddiqui, Serafim Batzoglou
Journal: Cancer Research (2022)

Abstract Our ~20,000 genes encode over one million protein variants, given alternative splice forms, allelic variation, and protein modification. Though large-scale genomics studies have expanded our understanding of biology, similarly, scaled deep and untargeted proteomics studies of biofluids have remained impractical due to complex workflows. To address this need, we have previously described Proteograph࣪, a novel platform that leverages the protein-corona interactions of nanoparticles for deep and untargeted proteomic sampling at scale. Using Proteograph࣪ in a non-small cell lung cancer (NSCLC) cohort, we previously conducted a deep interrogation of plasma from 141 subjects: 61 early-stage NSCLC subjects and 80 non-cancer controls. We identified 2,499 plasma proteins, with 1,992 present in ≥ 25% of the samples. Leveraging this data, we created a biomarker classifier distinguishing NSCLC from controls with area under the receiver operating characteristic curve of 0.911. In this study, we now re-analyze the data with the more sensitive DIA-NN software to enhance protein depth while preserving the accuracy of the classifier. In addition, to show the added value of our platform in combination with genomic data, we integrate previously sequenced exome data with our proteomic data to build a multi-modal proteogenomic deep learning classifier. Our results outline proteogenomic workflows for robust biomarker discovery and cohort subtyping. The Proteograph࣪ platform interrogates the plasma proteome at previously impractical combinations of scale, depth and coverage, and enables the development of improved classification models and the study of proteogenomics. 1Blume et al. Nat. Comm. (2020) Citation Format: Mahdi Zamanighomi, Harendra Guturu, Jian Wang, Amir Alavi, Tristan Brown, Daniel Hornburg, Moaraj Hasan, Shadi Ferdosi, Khatereh Motamedchaboki, Margaret Donovan, Theodore Platt, Ryan Benz, Asim Siddiqui, Serafim Batzoglou. Deep plasma proteomics at scale enabling proteogenomic analyses in a lung cancer (NSCLC) study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6339.
Changes in Glucose Metabolism and Glycemic Status With Once-Weekly Subcutaneous Semaglutide 2.4 mg Among Participants With Prediabetes in the STEP Program
Authors: Leigh Perreault, Melanie Davies, Juan P. Frias, Peter Nørkjaer Laursen, Ildiko Lingvay, Sriram Machineni, Anette Varbo, John P.H. Wilding, Signe Olrik Rytter Wallenstein, Carel W. le Roux
Journal: Diabetes Care (2022)

OBJECTIVE This analysis of 3,375 adults with overweight/obesity across the Semaglutide Treatment Effect in People with obesity (STEP) 1, 3, and 4 trials evaluated whether more participants with prediabetes had normoglycemia after 68 weeks’ treatment with once-weekly semaglutide 2.4 mg plus lifestyle intervention versus placebo and assessed changes in glucose metabolism in participants with prediabetes. RESEARCH DESIGN AND METHODS STEP 1, 3, and 4 were phase 3, 68-week, randomized, placebo-controlled, multinational trials; STEP 4 had a 20-week semaglutide run-in and 48-week randomized period. Analyses included changes (week 0–68; before the washout period) in glycemic status (prespecified: STEP 1 and 3; post hoc: STEP 4), and in HbA1c, fasting plasma glucose (FPG), and HOMA insulin resistance (HOMA-IR) among participants with prediabetes (post hoc). RESULTS Significantly more participants with baseline (week 0) prediabetes (n = 1,536) had normoglycemia at week 68 with semaglutide versus placebo (STEP 1, 84.1% vs. 47.8%; STEP 3, 89.5% vs. 55.0%; STEP 4, 89.8% vs. 70.4%; all P &amp;lt; 0.0001). Fewer participants with baseline normoglycemia had prediabetes at week 68 with semaglutide versus placebo (STEP 1, 2.9% vs. 10.9%; STEP 3, 3.2% vs. 5.8%; STEP 4, 1.1% vs. 5.0%). Semaglutide resulted in greater improvements in HbA1c, FPG, and HOMA-IR than placebo among participants with baseline prediabetes (all P &amp;lt; 0.01). CONCLUSIONS STEP 1, 3, and 4 collectively provide a robust assessment of the effects of semaglutide on glucose metabolism and prediabetes in a large cohort of adults with overweight/obesity while on treatment. Among participants with baseline prediabetes, 68 weeks’ treatment with semaglutide versus placebo led to significant improvements in glucose metabolism and a higher likelihood of normoglycemia.
Letter to the editor: The significant difference between East Asian and Western nondrinkers
Authors: Bossng Kang
Journal: Hepatology (2022)

To the editor, I read with interest the paper by Kim and colleagues[1] on the genetic backgrounds contributing to the divergence in individual Korean susceptibility to alcohol‐induced liver damage. I commend the authors who conducted this study. However, there is one thing that readers should be aware of. When comparing the results of this study with similar studies targeting Westerners, the characteristics of alcohol metabolism in East Asians must be taken into account.[2,3] Ethanol is converted to acetaldehyde by alcohol dehydrogenase in the body, and acetaldehyde is converted to acetic acid by aldehyde dehydrogenase2 (ALDH2). However, in people with a genetically low enzyme activity of ALDH2, the blood level of acetaldehyde soars immediately after drinking even a small amount of alcohol. This causes unpleasant body reactions such as headache, nausea, palpitation, facial flushing, and drowsiness, which is known to be the main cause of nondrinkers.[2,3] Although it is very rare for European descent to have a genetic deficiency of ALDH2, in East Asians represented by people from Korea, China, and Japan, such cases account for as many as 30%–40% of the total population.[4,5] In other words, it is thought that the group of nondrinkers in this study—the ND group—had a significantly higher proportion of people who were genetically‐deficient with ALDH2, whereas the group of heavy drinkers—the HD group—had a very small proportion. This difference in alcohol metabolism between the two groups, specifically in the ability to metabolize acetaldehyde, is not observed in people with European origin. CONFLICT OF INTEREST Nothing to report.
An analysis of proteogenomics and how and when transcriptome-informed reduction of protein databases can enhance eukaryotic proteomics
Authors: Laura Fancello, Thomas Burger
Journal: Genome biology (2022)

Abstract Background Proteogenomics aims to identify variant or unknown proteins in bottom-up proteomics, by searching transcriptome- or genome-derived custom protein databases. However, empirical observations reveal that these large proteogenomic databases produce lower-sensitivity peptide identifications. Various strategies have been proposed to avoid this, including the generation of reduced transcriptome-informed protein databases, which only contain proteins whose transcripts are detected in the sample-matched transcriptome. These were found to increase peptide identification sensitivity. Here, we present a detailed evaluation of this approach. Results We establish that the increased sensitivity in peptide identification is in fact a statistical artifact, directly resulting from the limited capability of target-decoy competition to accurately model incorrect target matches when using excessively small databases. As anti-conservative false discovery rates (FDRs) are likely to hamper the robustness of the resulting biological conclusions, we advocate for alternative FDR control methods that are less sensitive to database size. Nevertheless, reduced transcriptome-informed databases are useful, as they reduce the ambiguity of protein identifications, yielding fewer shared peptides. Furthermore, searching the reference database and subsequently filtering proteins whose transcripts are not expressed reduces protein identification ambiguity to a similar extent, but is more transparent and reproducible. Conclusions In summary, using transcriptome information is an interesting strategy that has not been promoted for the right reasons. While the increase in peptide identifications from searching reduced transcriptome-informed databases is an artifact caused by the use of an FDR control method unsuitable to excessively small databases, transcriptome information can reduce the ambiguity of protein identifications.